Low-Dose Doxepin For Treatment Of Sleep Disorders In Elderly Patients

ABSTRACT

Methods of treating sleep disorders, particularly certain aspects of insomnia, in elderly patients (65 years and older) by administering initial daily dosages of doxepin of 1-3 mg. These ultra-low initial dosages are more effective in elderly versus non-elderly patients in decreasing wake time during sleep, latency to persistent sleep and wake time after sleep, and are particularly efficacious in treating those conditions in the last hour of an 8-hour sleep cycle. Also, the dosages described herein are safe for elderly individuals.

RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.13/102,985, filed May 6, 2011, which is a continuation of U.S. patentapplication Ser. No. 11/804,722, filed May 18, 2007, which claimspriority under 35 U.S.C. 119 to U.S. Provisional Application No.60/801,821 filed May 19, 2006, the entire contents of which areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to the use of ultra-low doses of doxepin(1-3 milligrams) for treatment of sleep disorders, particularlyinsomnia, in individuals 65 years or older.

BACKGROUND OF THE INVENTION

Sleep is essential for health and quality of life. Insomnia is a growinghealth problem in the United States. It is believed that more than 10-15million people suffer from chronic insomnia and up to an additional 70million people suffer from some form of insomnia each year. Insomnia isa condition characterized by difficulty falling asleep (sleep onset),waking frequently during the night (fragmented sleep), waking too early(premature final awakening), and/or waking up feeling un-refreshed. Inthe National Sleep Foundation's (NSF) Sleep in America Poll 2005, 42% ofsurvey respondents reported that they awoke frequently during the night,22% of adults reported waking too early and not being able to return tosleep and 38% reported waking and feeling un-refreshed.

Sleep maintenance difficulty is a significant problem for many primarycare patients with chronic insomnia, including depressed patients,medically ill populations, especially those with pain symptoms, and theelderly.

In elderly populations (i.e., patients over the age of 65 years), thereare several sleep disorders that are often difficult to satisfactorilyaddress or manage with available medications. Many elderly patientssuffer from premature final awakening or terminal insomnia, in whichthey awaken for the day prior to the end of a normal 8-hour sleepperiod. Although some conventional medications can extend sleep time,they often fail to satisfactorily address the issue. In some instances,sleep is not extended into the final (eighth) hour of the sleep period,so that the patient still prematurely terminate sleep prior to the endof the sleep period, particularly during the last hour of an 8-hourperiod. If the dosage of medication is sufficient to extend sleep intoor through the eighth hour of the sleep period, the patients oftensuffer from post-sleep amnesia or memory loss, or experience sedationafter awakening that can interfere with normal activities, includingdriving, operation of other equipment, concentration, and normal mentalfunction.

Other elderly patients suffer from fragmented sleep in the final hour ofsleep, exhibiting disturbed sleep patterns that interfere with restfulsleep. Although fragmented sleep can be facilitated by a number ofcommercially-available sleep medications, many of those do notadequately improve sleep efficiency in the last hour of an 8-hour sleepperiod. As with treatments for terminal insomnia, if the dosage isincreased sufficiently to improve sleep efficiency in the last hour ofthe sleep period, the patient may experience post-sleep sedation thatinterferes with normal activities.

Older patients are at particular risk for common side effects ofconventional insomnia therapy, including next-day amnesia or memoryloss, next-day sedation, and drug-drug interactions between sleepmedications and other medications they may be taking.

Benzodiazepines and two of the most frequently used non-benzodiazepineagents in the treatment of insomnia, zolpidem and zaleplon, act throughgamma-amino butyric acid (GABA) receptor inhibition and are consideredto be Schedule IV drugs which have some risk of abuse and can lead tolimited physical or psychological dependence. Two over-the-counterantihistamines often used for treatment of insomnia, diphenhydramine anddoxylamine, have substantial anticholinergic properties, with thepotential to cause numerous side effects, especially among olderpatients.

Doxepin HCl is a tricyclic compound currently approved for treatment ofdepression. The recommended daily dose for the treatment of depressionranges from 75 mg to 300 mg. Doxepin, unlike most FDA approved productsfor the treatment of insomnia, is not a Schedule IV controlledsubstance.

U.S. Pat. Nos. 5,502,047 and 6,211,229, the entire contents of which areincorporated herein by reference, describe the use of doxepin forchronic and transient/short term insomnia, respectively, at dosages farbelow those used to treat depression. However, the mean half-life ofdoxepin is 17 hours, and the half-life of its major active metabolite,desmethyldoxepin, is 51 hours. Thus, when taken at the start of a sleepperiod, a majority of the drug or active metabolite should still bepresent in the body at the end of the sleep period. As a result, itwould be expected that dosages of doxepin that are sufficient to addressterminal insomnia or last-hour fragmented sleep in the elderly wouldalso cause post-sleep sedation or other undesirable adverse effects.

The present invention describes the surprising ability of ultra-low dosedoxepin (1-3 mg) to treat last-hour fragmented sleep and prematureawakening in patients 65 years of age and older, without untoward sideeffects. Also, described is the use of doses between about 1 and 6 mgfor the treatment of certain sleep conditions in a patient 65 years ofage or older.

SUMMARY OF THE INVENTION

Some embodiments provide methods for treating insomnia in an elderlypatient. In some embodiments, the methods include administering to apatient over the age of 65 an initial daily dosage of 1 mg doxepin, apharmaceutically acceptable salt or a prodrug thereof; evaluatingwhether a desired improvement in sleep is achieved by the patient at theinitial dosage; and if the desired improvement in sleep is not achieved,increasing the dosage of doxepin, the salt or the prodrug thereofincrementally until the desired dosage is achieved or until a maximumdesired dosage is reached. In one aspect of the embodiment, the maximumdesired dosage is selected from the group consisting of 1.5, 2, 2.5, and3 milligrams. In some aspects, the initial dose can be 0.5 mg, forexample.

Some embodiments provide methods for treating insomnia in an elderlyindividual at risk for amnesia or memory impairment resulting from sleepmedication. In an embodiment, the methods include identifying anindividual over the age of 65 that is at risk of or suffering fromamnesia or memory impairment resulting from a sleep medication;administering to the individual an initial daily dosage of 1 milligramdoxepin, a pharmaceutically acceptable salt or a prodrug thereof;evaluating whether a desired improvement in sleep or in avoidance ofamnesia or memory impairment is achieved by the individual at theinitial dosage; and if the desired improvement in sleep or in avoidanceof amnesia or memory impairment is not achieved, increasing the dosageof doxepin, the salt, or the prodrug incrementally until the desireddosage is achieved or until a maximum desired dosage is reached. In oneaspect of the embodiment. the maximum desired dosage is selected fromthe group consisting of 1.5, 2, 2.5, and 3 milligrams. In some aspects,the initial dose can be 0.5 mg, for example.

Some embodiments provide methods of decreasing wake time during sleep(WTDS) in a patient over the age of 65. In an embodiment, the methodsinclude administering to the patient an initial daily dosage of 1 mgdoxepin, a pharmaceutically acceptable salt or a prodrug thereof;evaluating whether a desired improvement in WTDS is achieved by theindividual at the initial dosage; and if the desired improvement is notachieved, increasing the dosage of doxepin, the salt, or the prodrugincrementally until the desired dosage is achieved or until a maximumdesired dosage is reached. In some embodiments. the maximum desireddosage is selected from the group consisting of 1.5, 2, 2.5, and 3milligrams. In some aspects, the initial dose can be 0.5 mg, forexample.

Some embodiments provide methods of decreasing latency to persistentsleep (LPS) in a patient over the age of 65. In some embodiments, themethods include administering to the patient an initial daily dosage of3 mg doxepin, a pharmaceutically acceptable salt or a prodrug thereof.In some aspects, the initial dose can be 0.5 mg, 0.1, or 0.2 mg forexample.

Some embodiments relate to methods for treating a sleep disorder, whichmethods can include identifying a patient over the age of 65 who issusceptible to one or more of the following side effects caused by sleepmedication: nervous system side effects; psychiatric side effects;respiratory side effects; skin side effects; musculoskeletal sideeffects; and connective tissue side effects; and administering doxepin,pharmaceutically acceptable salts of the same, or prodrugs of the sameto the patient. Preferably, the dosage can be about 1 mg to 6 mg. Theidentifying step can include identifying a patient who is susceptible tocentral nervous system side effects caused by sleep medication, and thecentral nervous system side effect can be, for example, at least one ofsomnolence, headache, dizziness, lethargy, and balance disorder. Also,the identifying step can include identifying a patient who issusceptible to psychiatric side effects caused by sleep medication. Thepsychiatric side effect can be, for example, at least one of anxiety,confusion, and abnormal dreams. In some aspects, the dose can be about0.5 mg to about 10 mg, for example.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the different parameters that can be analyzed usingpolysomnography.

FIG. 2 is a graph showing the doxepin plasma profile concentration atvarious time points for 1 mg, 3 mg and 6 mg doxepin.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the invention relates to the ability of ultra-low-dosedoxepin, pharmaceutically acceptable salts thereof or prodrugs thereofto treat fragmented sleep in the last hour of a sleep period, inparticular an 8-hour sleep period and/or to treat premature finalawakening (terminal insomnia) in the last hour of the sleep period in anelderly individual (65 years and older) by identifying an individual inneed of such treatment, and providing an ultra-low dose of doxepin, apharmaceutically acceptable salt thereof, or a prodrug thereof to theindividual. Another aspect of the invention relates to treatment ofelderly insomnia patients at risk for or desirous or reducing oravoiding post-sleep amnesia or memory loss resulting from sleepmedication. It has been surprisingly discovered that an ultra-low doseof doxepin, particularly an initial dose of 1 mg, is more effective inpatients 65 years and older than in younger adults. The term “ultra-lowdose” refers to an initial daily dose of 1 mg and an ultimate daily dosebetween about 1 mg and 3 mg. In some embodiments, ultimate daily dosagesof doxepin are about 1.5 mg, 2 mg or 2.5 mg. These ultra-low dosageshave reduced side effects, are surprisingly effective, and have arelatively rapid onset. In some aspects, the final dose given or used totreat an elderly individual can be, for example, 4 mg, 5, mg or 6 mg. Insome aspects, the initial dose used to treat an elderly individual canbe 0.5 milligrams, for example.

In contrast to the treatment of primary insomnia in elderly patients ingeneral and treatment of elderly individuals with the specific sleepdisorders or side effect issues discussed above with an initial dose of1 mg doxepin, it appears that the initial dose for treating non-elderlyadult patients is more advantageously 3 mg or 6 mg. The efficacy of a 1mg dosage for at least some insomnia treatments in elderly patients isbelieved to be surprising and is also believed to provide importantadvantages in treating insomnia in selected elderly patient populations.

DEFINITIONS

As used herein, the term “polysomnography” (PSG) refers a diagnostictest during which a number of physiologic variables are measured andrecorded during sleep. Physiologic sensor leads are placed on thepatient in order to record brain electrical activity, eye and jaw musclemovement, leg muscle movement, airflow, respiratory effort (chest andabdominal excursion), EKG and oxygen saturation Information is gatheredfrom all leads and fed into a computer and outputted as a series ofwaveform tracings which enable the technician to visualize the variouswaveforms, assign a score for the test, and assist in the diagnosticprocess. The primary efficacy variable, wake time during sleep (WTDS)and various secondary efficacy variables are all based on the PSG andare defined as follows.

“Wake Time During Sleep” (WTDS), typically expressed in minutes, is thenumber of wake events (epochs) after the onset of persistent sleep andprior to final awakening, divided by two. Each epoch is defined as a30-second duration on the PSG recording.

“Wake Time After Sleep” (WTAS) , typically expressed in minutes, is thenumber of epochs after the final awakening until the end of PSGrecording (i.e., a wake epoch immediately prior to the end of therecording), divided by two. If the patient does not have a wake epochimmediately prior to the end of the recording, then WTAS is zero.

“Wake After Sleep Onset” (WASO) is the sum of WTDS and WTAS.

“sWASO” refers to subjective wake after sleep onset (WASO).

“Latency to Persistent Sleep” (LPS) , typically expressed in minutes, isthe number of epochs from the beginning of the PSG recording(lights-out) to the start of the first 20 consecutive non-wake epochs,divided by two.

“Total Sleep Time” (TST) typically expressed in minutes, is the numberof non-wake epochs from the beginning of the PSG recording to the end ofthe recording, divided by two.

“sTST” refers to subjective total sleep time.

“Sleep Efficiency” (SE) is the TST divided by the time in bed (8 hours),multiplied by 100 and expressed as a percentage. This also can bedivided into SE for each third-of-the-night of sleep, reflecting the SEfor each 160 minute time interval across the night. Finally, SE can bemeasured for individual hours during the night or sleep period, forexample the final hour of the sleep period.

“NAASO” refers to the number of awakenings after sleep onset.

“sNAASO” refers to subjective NAASO.

“LSO” refers to “latency to sleep onset, typically expressed in minutes.

The term “fragmented sleep” can refer to interrupted sleep over ameasurement period or sleep period, for example the time a patient isawake during period of measurement. Fragmentation can occur as a resultof multiple awakenings or one or more awakenings of a long duration.

The term “prodrug” refers to an agent that is converted into the activedrug in vivo. Prodrugs are often useful because, in some situations,they may be easier to administer than the active drug. They may, forinstance, be bioavailable by oral administration whereas the active drugis not. The prodrug may also have improved solubility in pharmaceuticalcompositions over the active drug. An example, without limitation, of aprodrug would be a compound of the present invention which isadministered as an ester (the “prodrug”) to facilitate transmittalacross a cell membrane where water solubility is detrimental to mobilitybut which then is metabolically hydrolyzed to the carboxylic acid, theactive entity, once inside the cell where water-solubility isbeneficial. A further example of a prodrug might be a short peptide(polyaminoacid) bonded to an acid group where the peptide is metabolizedto reveal the active moiety.

The term “pharmaceutically acceptable salt” refers to an ionic form of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. Pharmaceutical salts can be obtained byreacting a compound of the invention with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. Pharmaceuticalsalts can also be obtained by reacting a compound of the invention witha base to form a salt such as an ammonium salt, an alkali metal salt,such as a sodium or a potassium salt, an alkaline earth metal salt, suchas a calcium or a magnesium salt, a salt of organic bases such asdicyclohexylamine, N-methyl-D-glutamine, tris(hydroxymethyl)methylamine,and salts with amino acids such as arginine, lysine, and the like.

Compounds Doxepin:

Doxepin HCl is a tricyclic compound currently approved and available fortreatment of depression and anxiety. Doxepin has the followingstructure:

Doxepin belongs to a class of psychotherapeutic agents known asdibenzoxepin tricyclic compounds, and is currently approved andprescribed for use as an antidepressant to treat depression and anxiety.Doxepin has a well-established safety profile, having been prescribedfor over 35 years.

Doxepin, unlike most FDA approved products for the treatment ofinsomnia, is not a Schedule IV controlled substance. U.S. Pat. Nos.5,502,047 and 6,211,229, the entire contents of which are incorporatedherein by reference, describe the use of doxepin for the treatmentchronic and non-chronic (e.g., transient/short term) insomnias atdosages far below those used to treat depression.

It is contemplated that doxepin for use in the methods described hereincan be obtained from any suitable source or made by any suitable method.As mentioned, doxepin is approved and available in higher doses (75-300milligrams) for the treatment of depression and anxiety. Doxepin HCl isavailable commercially and may be obtained in capsule form from a numberof sources. Doxepin is marketed under the commercial name SINEQUAN® andin generic form, and can be obtained in the United States generally frompharmacies in capsule form in amounts of 10, 25, 50, 75, 100 and 150 mgdosage, and in liquid concentrate form at 10 mg/mL. Doxepin HCl can beobtained from Plantex Ltd. Chemical Industries (Hakadar Street,Industrial Zone, P.O. Box 160, Netanya 42101, Israel), Sifavitor S.p.A.(Via Livelli 1—Frazione, Mairano, Italy), or from Dipharma S.p.A. (20021Baranzatc di Bollate, Milano, Italy). Also, doxepin is commerciallyavailable from PharmacyRx (NZ) (2820 1^(st) Avenue, Castlegar. B.C.,Canada) in capsule form in amounts of 10, 25, 50, 75, 100 and 150 mg.Furthermore, Doxepin HCl is available in capsule form in amounts of 10,25, 50, 75, 100 and 150 mg and in a 10 mg/ml liquid concentrate from CVSOnline Pharmacy Store (CVS.com).

Also, doxepin can be prepared according to the method described in U.S.Pat. No. 3,438,981, which is incorporated herein by reference in itsentirety. As another illustration, doxepin can be prepared from11-[3-(Dimnethylamino)propyl]-6,11-dihydrodibenzo[b,c]oxepin-11-ol astaught in U.S. Pat. No. 3,420,851, which is incorporated herein byreference in its entirety It should be noted and understood thatalthough many of the embodiments described herein specifically refer to“doxepin,” other doxepin-related compounds can also be used, including,for example, pharmaceutically acceptable salts, prodrugs, metabolites,in-situ salts of doxepin formed after administration, and solid stateforms, including polymorphs and hydrates.

Metabolites:

In addition, doxepin metabolites can be prepared and used. By way ofillustration, some examples of metabolites of doxepin can include, butarc not limited to, desmethyldoxepin, hydroxydoxepin,hydroxyl-N-desmethyldoxepin, doxepin N-oxide,N-acetyl-N-desmethyldoxepin, N-desmethyl-N-formyldoxepin, quaternaryammonium-linked glucuronide, 2-O-glucuronyldoxepin, didesmethyldoxepin,3-O-glucuronyldoxepin, or N-acetyldidesmethyldoxepin. The metabolites ofdoxepin can be obtained or made by any suitable method, including themethods described above for doxepin.

Desmethyldoxepin has the following structure:

Desmethyldoxepin is commercially available as a forensic standard. Forexample, it can be obtained from Cambridge Isotope Laboratories, Inc.(50 Frontage Road, Andover, Mass.). Desmethyldoxepin for use in themethods discussed herein can be prepared by any suitable procedure. Forexample, desmethyldoxepin can be prepared from 3-methylaminopropyltriphenylphosphonium bromide hydrobromide and6,11-dihydrodibenz(b,c)oxepin-11-one according to the method taught inU.S. Pat. No. 3,509,175, which is incorporated herein by reference inits entirety.

Hydroxydoxepin has the following structure:

2-Hydroxydoxepin can be prepared by any suitable method, including astaught by Shu et al. (Drug Metabolism and Disposition (1990)18:735-741), which is incorporated herein by reference in its entirety.

Hydroxyl-N-desrnethyldoxepin has the following structure:

2-Hydroxy-N-desmethyldoxepin can be prepared any suitable method.

Doxepin N-oxide has the following structure:

Doxepin N-oxide can be prepared by any suitable method. For example,doxepin N-oxide can be prepared as taught by Hobbs (Biochem Pharmacol(1969) 18:1941-1954), which is hereby incorporated by reference in itsentirety.

N-acetyl-N-desmethyldoxepin has the following structure:

N-acetyl-N-desmethyldoxepin can be prepared by any suitable means. Forexample, (E)-N-acetyl-N-desmethyldoxepin has been produced infilamentous fungus incubated with doxepin as taught by Moody et al.(Drug Metabolism and Disposition (1999) 27:1157-1164), herebyincorporated by reference in its entirety.

N-desmethyl-N-formyldoxepin has the following structure:

N-desmethyl-N-formyldoxepin can be prepared by any suitable means. Forexample, (E)-N-desmethyl-N-formyldoxepin has been produced infilamentous fungus incubated with doxepin as taught by Moody et al.(Drug Metabolism and Disposition (1999) 27:1157-1164), herebyincorporated by reference in its entirety.

N-acetyldidesmethyldoxepin has the following structure:

N-acetyldidesmethyldoxepin can be prepared by any suitable means. Forexample, (E)-N-acetyldidesmethyldoxepin has been produced in filamentousfungus incubated with doxepin as taught by Moody et al. (Drug Metabolismand Disposition (1999) 27:1157-1164), hereby incorporated by referencein its entirety.

Didesmethyldoxepin has the following structure:

Didesmethyldoxepin can be prepared by any suitable means. For example,(Z)- and (E)-didesmethyldoxepin have been isolated from plasma andcerebrospinal fluid of depressed patients taking doxepin, as taught byDeuschle et al. (Psychopharmacology (1997) 131:19-22), herebyincorporated by reference in its entirety.

3-O-glucuronyldoxepin has the following structure:

3-O-glucuronyldoxepin can be prepared by any suitable means. Forexample, (E)-3-O-glucuronyldoxepin has been isolated from the bile ofrats given doxepin, as described by Shu et al. (Drug Metabolism andDisposition (1990)18:1096-1099), hereby incorporated by reference in itsentirety.

2-O-glucuronyldoxepin has the following structure:

2-O-glucuronyldoxepin can be prepared by any suitable means. Forexample, (E)-2-O-glucuronyldoxepin has been isolated from the bile ofrats given doxepin, and also in the urine of humans given doxepin, asdescribed by Shu et al. (Drug Metabolism and Disposition (1990)18:1096-1099), hereby incorporated by reference in its entirety.

Quaternary ammonium-linked glucuronide of doxepin (doxepinN⁺-glucuronide) has the following structure:

N⁺-glucuronide can be obtained by any suitable means. For example,doxepin N⁺-glucuronide can be prepared as taught by Luo et al. (DrugMetabolism and Disposition, (1991) 19:722-724), hereby incorporated byreference in its entirety.

Methods of Treating an Elderly Individual

In one embodiment of the present invention an individual who is at least65 years of age who has insomnia is given an initial daily dosage ofabout 1 mg doxepin. It should be noted that in any of the methodsdescribed herein, a doxepin metabolite, prodrug or pharmaceuticallyacceptable salt thereof may be used in place of doxepin. If the desiredimprovement in sleep is not achieved, then the dosage may beincrementally increased until the desired dosage is achieved or until amaximum desired dosage is reached which may be, for example, 1.5 mg, 2mg or 3 mg. Doxepin at the dosages described above demonstratedincreased efficacy on objective and subjective sleep maintenanceparameters in elderly individuals.

In another embodiment, an individual who is at least 65 years of age andis at risk for amnesia or memory impairment resulting from taking sleepmedication can be treated. The methods of treatment can include, forexample, identifying an individual over the age of 65 that is at risk orsuffering from amnesia or memory impairment resulting from a sleepmedication; administering an initial dose of 1 mg doxepin to theindividual; and evaluating whether a desired improvement in sleep isachieved, for example, a reduction in or lack of amnesia or memoryimpairment, for example, compared to the previous sleep medication.Further, if the desired improvement is not achieved, the methods caninclude the step of increasing the dosage. For example, the dosage canbe increased to 1.5, 2, 2.5 or 3 milligrams. In some aspects, the dosagecan be increased to 4, 5 or 6 milligrams.

In another embodiment, an individual who is at least 65 years of age andwho suffers from premature or early awakening or terminal insomnia canbe treated. The methods of treatment can include, for example,identifying an individual over the age of 65 that is at suffers frompremature early awakening; administering an initial dose of 1 mg doxepinto the individual; and evaluating whether a desired improvement inawakening is achieved, for example, a later final awakening. Also, ifthe desired improvement is not achieved, the methods can include thestep of increasing the dosage. For example, the dosage can be increasedto 1.5, 2, 2.5 or 3 milligrams. In some aspects, the dosage can beincreased to 4.5 or 6 milligrams.

Also, in another embodiment, an individual who is at least 65 years ofage and who suffers from fragmented sleep in the 8^(th) hour of a sleepperiod can be treated. The methods of treatment can include, forexample, identifying an individual over the age of 65 that is at suffersfrom fragmented sleep for the 8^(th) hour of a sleep period;administering an initial dose of 1 mg doxepin to the individual; andevaluating whether a desired improvement in sleep is achieved in the8^(th) hour of the sleep period, for example, a reduction in the numberand/or duration of awakenings. Also, if the desired improvement is notachieved, the methods can include the step of increasing the dosage. Forexample, the dosage can be increased to 1.5, 2, 2.5 or 3 milligrams. Insome aspects, the dosage can be increased to 4, 5 or 6 milligrams.

In another embodiment, an individual who is at least 65 years of age andis in need of decreased WTDS is identified and is given an initial dailydosage of about 1 mg doxepin. If the desired improvement in sleep is notachieved, then the dosage may be incrementally increased until thedesired dosage is achieved or until a maximum desired dosage is reachedwhich may be, for example, 1.5 mg, 2 mg or 3 mg.

In another embodiment, an individual who is at least 65 years of age andis in need of decreased LPS is identified and is given an initial dailydosage of about 3 mg doxepin. If the desired improvement in sleep is notachieved, then the dosage may be incrementally increased until thedesired dosage is achieved or until a maximum desired dosage is reachedwhich may be, for example, 3.5, 4, 4.5, 5, 5.5 or 6 mg.

In another embodiment, an individual who is at least 65 years of age andis in need of decreased WTAS is identified and is given an initial dailydosage of about 1 mg or 3 mg doxepin. If the desired improvement insleep is not achieved, then the dosage may be incrementally increaseduntil the desired dosage is achieved or until a maximum desired dosageis reached which may be, for example, 3.5, 4, 4.5, 5 or 5.5 mg.

Some embodiments relate to methods for treating a sleep disorder, whichmethods can include identifying a patient over the age of 65 who issusceptible to one or more of the following side effects caused by sleepmedication: nervous system side effects; psychiatric side effects;respiratory side effects; skin side effects; musculoskeletal sideeffects; and connective tissue side effects; and administering doxepin,pharmaceutically acceptable salts of the same, or prodrugs of the sameto the patient. Preferably, the dosage can be about 1 mg to 6 mg. Theidentifying step can include identifying a patient who is susceptible tocentral nervous system side effects caused by sleep medication, and thecentral nervous system side effect can be, for example, at least one ofsomnolence, headache, dizziness, lethargy, and balance disorder. Also,the identifying step can include identifying a patient who issusceptible to psychiatric side effects caused by sleep medication. Thepsychiatric side effect can be, for example, at least one of anxiety,confusion, and abnormal dreams.

The methods described herein can be used to treat an individual that is65 years of age or older, suffering from a sleep disorder, such asinsomnia. The individual can suffer from a chronic insomnia or anon-chronic insomnia. For chronic (e.g., greater than 3-4 weeks) ornon-chronic insomnias, a patient may suffer from difficulties in sleeponset, sleep maintenance (interruption of sleep during the night byperiods of wakefulness), sleep duration, sleep efficiency, prematureearly-morning awakening, or a combination thereof. Also, the insomniamay be attributable to the concurrent use of other medication, forexample. The non-chronic insomnia can be, for example, a short terminsomnia or a transient insomnia. The chronic or non-chronic insomniacan be a primary insomnia or an insomnia that is secondary orattributable to another condition, for example a disease such asdepression or chronic fatigue syndrome. In some aspects, the patient canone that is not suffering from an insomnia that is a component of adisease, or a patient can be treated that is otherwise healthy. Aspreviously mentioned, the chronic or non-chronic insomnia can be aprimary insomnia, that is, one that is not attributable to anothermental disorder, a general medical condition, or a substance. In manycases, such conditions may be associated with a chronic insomnia and caninclude, but are not limited to, insomnia attributable to a diagnosableDSM-IV disorder, a disorder such as anxiety or depression, or adisturbance of the physiological sleep-wake system. In some aspects theinsomnia can be non-chronic, or of short duration (e.g., less than 3-4weeks). Examples of causes of such insomnia may be extrinsic orintrinsic and include, but arc not limited to environmental sleepdisorders as defined by the International Classification of SleepDisorders (ICSD) such as inadequate sleep hygiene, altitude insomnia oradjustment sleep disorder. Also, short-term insomnia may also be causedby disturbances such as shift-work sleep disorder.

Administration of Doxepin

In performing the methods, doxepin, a pharmaceutically acceptable saltof doxepin, or prodrug of doxepin can be administered using any suitableroute or method of delivery. Also, doxepin, a pharmaceuticallyacceptable salt or a prodrug thereof can be included and administered ina composition.

Suitable routes of administration include oral, buccal, sublingual,transdermal, rectal, topical, transmucosal, or intestinaladministration; parenteral delivery, including intramuscular,subcutaneous, intravenous, intramedullary injections, as well asintrathecal, direct intraventricular, intraperitoneal, intranasal, orintraocular injections.

For oral administration, the compounds can be formulated readily bycombining the active compounds with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the compounds of theinvention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Administration though oralpathways can be accomplished, for example, using a capsule, a tablet, agranule, a spray, a syrup, a liquid, powder, granules, pastes (e.g., forapplication to the tongue). Oral administration can be accomplishedusing fast-melt formulations, for example. Pharmaceutical preparationsfor oral use can be obtained by mixing one or more solid excipient withpharmaceutical combination of the invention, optionally grinding theresulting mixture, and processing the mixture of granules, after addingsuitable auxiliaries, if desired, to obtain tablets or dragee cores.Suitable excipients are, in particular, fillers such as sugars,including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations such as, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone (PVP). If desired, disintegrating agents may beadded, such as the cross-linked polyvinyl pyrrolidone, agar, or alginicacid or a salt thereof such as sodium alginate.

Pharmaceutical preparations which can be used orally, includingsublingually, include for example, liquid solutions, powders, andsuspensions in bulk or unit dosage forms. Also, the oral formulationscan include, for example, pills, tablets, granules, sprays, syrups,pastes, powders, boluses, pre-measured ampules or syringes, push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

For buccal administration, the compositions may take any suitable form,for example, tablets or lozenges.

For topical administration, the compounds may be formulated foradministration to the epidermis as ointments, gels, creams, pastes,salves, gels, creams or lotions, or as a transdermal patch. Ointmentsand creams may, for example, be formulated with an aqueous or oily basewith the addition of suitable thickening and/or gelling agents. Lotionsmay be formulated with an aqueous or oily base and will in general alsocontaining one or more emulsifying agents, stabilizing agents,dispersing agents, suspending agents, thickening agents, or coloringagents.

For injection, the agents of the invention may be formulated in aqueoussolutions, preferably in physiologically compatible buffers such asHanks's solution, Ringer's solution, or physiological saline buffer. Fortransmucosal administration, penetrants appropriate to the barrier to bepermeated are used in the formulation. Such penetrants are generallyknown in the art.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebulizer, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, orother suitable gas. In the case of a pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, e.g., gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

In addition, any of the compounds and compositions described herein canalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt. Furthermore, any of the compounds andcompositions described herein also can be formulated as a fast-meltpreparation. The compounds and compositions can also be formulated andadministered as a drip, a suppository, a salve, an ointment, anabsorbable material such a transdermal patch, or the like.

One can also administer the compounds of the invention in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can be foundin the incorporated materials in Remington: The Science and Practice ofPharmacy (20^(th) ed, Lippincott Williams & Wilkens Publishers (2003)),which is incorporated herein by reference in its entirety.

A variety of techniques for formulation and administration can be foundin Remington: The Science and Practice of Pharmacy (20^(th) ed,Lippincott Williams & Wilkens Publishers (2003)), which is incorporatedherein by reference in its entirety.

Compositions

As mentioned above, doxepin, pharmaceutically acceptable salts, and/orprodrugs of the same can be used alone or in combination with othersubstances, such as for example, other insomnia or sleep medications, orwith other medications that treat a primary illness. The doxepin aloneor in combination can be included as part of a composition. Thecompounds and compositions can include any suitable form of the compoundfor pharmaceutical delivery, as discussed in further detail herein.

The compositions and formulations disclosed herein also can include oneor more pharmaceutically acceptable carrier materials or excipients.Such compositions can be prepared for storage and for subsequentadministration. Acceptable carriers or diluents for therapeutic use arewell known in the pharmaceutical art, and are described, for example, inthe incorporated material of Remington: The Science and Practice ofPharmacy (20^(th) ed, Lippincott Williams & Wilkens Publishers (2003)),which is incorporated herein by reference in its entirety. The term“carrier” material or “excipient” herein can mean any substance, notitself a therapeutic agent, used as a carrier and/or diluent and/oradjuvant, or vehicle for delivery of a therapeutic agent to a subject oradded to a pharmaceutical composition to improve its handling or storageproperties or to permit or facilitate formation of a dose unit of thecomposition into a discrete article such as a capsule or tablet suitablefor oral administration. Excipients can include, by way of illustrationand not limitation, diluents, disintegrants, binding agents, adhesives,wetting agents, polymers, lubricants, glidants, substances added to maskor counteract a disagreeable taste or odor, flavors, dyes, fragrances,and substances added to improve appearance of the composition.Acceptable excipients include lactose, sucrose, starch powder, maizestarch or derivatives thereof, cellulose esters of alkanoic acids,cellulose alkyl esters, talc, stearic acid, magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, gelatin, acacia gum, sodium alginate, polyvinyl-pyrrolidone,and/or polyvinyl alcohol, saline, dextrose, mannitol, lactose, lecithin,albumin, sodium glutamate, cysteine hydrochloride, and the like.Examples of suitable excipients for soft gelatin capsules includevegetable oils, waxes, fats, semisolid and liquid polyols. Suitableexcipients for the preparation of solutions and syrups include, withoutlimitation, water, polyols, sucrose, invert sugar and glucose. Suitableexcipients for injectable solutions include, without limitation, water,alcohols, polyols, glycerol, and vegetable oils. The pharmaceuticalcompositions can additionally include preservatives, solubilizers,stabilizers, wetting agents, emulsifiers, sweeteners, colorants,flavorings, buffers, coating agents, or antioxidants. Sterilecompositions for injection can be formulated according to conventionalpharmaceutical practice as described in the incorporated material inRemington: The Science and Practice of Pharmacy (20^(th) ed, LippincottWilliams & Wilkens Publishers (2003)). For example, dissolution orsuspension of the active compound in a vehicle such as water ornaturally occurring vegetable oil like sesame, peanut, or cottonseed oilor a synthetic fatty vehicle like ethyl oleate or the like may bedesired. Buffers, preservatives, antioxidants and the like can beincorporated according to accepted pharmaceutical practice. The compoundcan also be made in microencapsulated form. In addition, if desired, theinjectable pharmaceutical compositions may contain minor amounts ofnontoxic auxiliary substances, such as wetting agents, pH bufferingagents, and the like. If desired, absorption enhancing preparations (forexample, liposomes), can be utilized.

The compositions and formulations can include any other agents thatprovide improved transfer, delivery, tolerance, and the like. Thesecompositions and formulations can include, for example, powders, pastes,ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic)containing vesicles (such as Lipofectin™), DNA conjugates, anhydrousabsorption pastes, oil-in-water and water-in-oil emulsions, emulsionscarbowax (polyethylene glycols of various molecular weights), semi-solidgels, and semi-solid mixtures containing carbowax. Any of the foregoingmixtures may be appropriate in treatments and therapies in accordancewith the present invention, provided that the active ingredient in theformulation is not inactivated by the formulation and the formulation isphysiologically compatible and tolerable with the route ofadministration. See also Baldrick P. “Pharmaceutical excipientdevelopment: the need for preclinical guidance.” Regul. Toxicol.Pharmacol. 32(2):210-8 (2000), Charman W N “Lipids, lipophilic drugs,and oral drug delivery-some emerging concepts.” J Pharm Sci.89(8):967-78 (2000), Powell et al. “Compendium of excipients forparenteral formulations” PDA J Pharm Sci Technol. 52:238-311 (1998) andthe citations therein for additional information related toformulations, excipients and carriers well known to pharmaceuticalchemists.

Dosage

As mentioned above, in some embodiments the preferable dosage can be anultra low dose between about 1 milligram and 3 milligrams. Preferably,the dosage can be about, 1 milligram, about 1.5 milligrams, about 2milligrams, about 2.5 milligrams, or about 3 milligrams. It should benoted that in some embodiments the dosage can be about 4 milligrams,about 5 milligrams, about 6 milligrams. In some embodiments, the dosagecan be between about 0.5 and 20 milligrams.

The selected dosage level can depend upon, for example, the route ofadministration, the severity of the condition being treated, and thecondition and prior medical history of the patient being treated.However, it is within the skill of the art to start doses of thecompound at levels lower than required to achieve the desiredtherapeutic effect and to gradually increase the dosage until thedesired effect is achieved. It will be understood, however, that thespecific dose level for any particular patient can depend upon a varietyof factors including the genetic makeup, body weight, general health,diet, time and route of administration, combination with other drugs andthe particular condition being treated, and its severity. For thetreatment of insomnia, preferably one dose is administered prior tobedtime.

The selected dosage can also be determined by targeting a mean plasmaconcentration profile that has been associated with improvement in oneor more PSG sleep variables including LPS, WASO, TST, SE, WTDS, or WTAS(FIG. 1). Examples of such plasma concentration profiles are shown inFIG. 2. The target plasma concentration profile may be achieved by anysuitable route of administration including oral, buccal, sublingual,transdermal, rectal, topical, transmucosal, or intestinaladministration; parenteral delivery, including intramuscular,subcutaneous, intravenous, intramedullary injections, as well asintrathecal, direct intraventricular, intraperitoneal, intranasal, orintraocular injections using any suitable formulation.

EXAMPLES Example 1 Study to Evaluate Sleep Maintenance Effects of ThreeDose Levels of Doxepin Hydrochloride (HCl) Relative To Placebo inElderly Patients With Primary Insomnia

A randomized, multi-center, double-blind, placebo-controlled,four-period crossover, dose-response study was designed to assess theeffects of doxepin (1 mg, 3 mg and 6 mg) compared with placebo inpatients aged 65 years or older with primary sleep maintenance insomnia.Patients received a single-blind placebo for two consecutive nightsduring the PSG screening period, and double-blind study drug for twoconsecutive nights during each of the four treatment periods. Followingeach study drug administration, patients had 8 continuous hours of PSGrecording in the sleep center. Patents were allowed to leave the sleepcenter during the day after each PSG assessment was complete. A 5- or12-day study drug-free interval separated each PSG assessment visit. Theduration of study participation per patient was approximately 7 to 11weeks.

Patients who qualified for study entry, based on the screening PSGassessments, were randomized to a treatment sequence using a Latinsquare design. A final study visit was performed for patients eitherafter completion of the four treatment periods or upon discontinuationfrom the study. Efficacy assessments were made at each visit and safetyassessments were performed throughout the study.

Seventy-one patients were included in the per-protocol analysis set. Themain inclusion criteria were male and/or female patients, aged 65 yearsor older, in good general health with at least a 3-month history ofDiagnostic and Statistical Manual of Mental Disorders, fourth Edition(DSM-IV)-defined primary insomnia, reporting each of the following onfour of seven nights prior to PSG screening: ≤6.5 hours of total sleeptime (TST). ≤60 min of wakefulness after sleep onset (WASO) and min oflatency to sleep onset (LSO). Doxepin HCl 1 mg, 3 mg and 6 mg capsules,and placebo capsules, were provided as a single dose for oraladministration.

The primary efficacy assessment was WTDS. Secondary efficacy assessmentsincluded WASO, SE, TST, LPS, and WTAS. All objective efficacyassessments were performed on Night 1 and Night 2 of each treatmentperiod.

Efficacy analyses used the per-protocol (PP; the primary analysis set)sets. The PP analysis set included all patients who did not haveimportant protocol derivations that would likely have effected theevaluation of efficacy, and who provided WTDS data from each of the fourtreatment periods. The primary and secondary efficacy analyses werebased on the PP analysis set.

Within each treatment period, the average of the two data points wasused for analysis, if applicable. The primary efficacy variable. WTDS,as well as the secondary objective and subjective efficacy parameterswere analyzed using an analysis of variance (ANOVA) model with terms forsequence, patient within sequence, treatment and period. Pairwisecomparisons of each active treatment versus placebo were performed usingDunnett's test.

All randomized patients who received at least one dose of double-blindstudy medication were included in the safety analyses, which were basedon observed data.

Efficacy Results Primary

WTDS exhibited a statistically significant decrease at the doxepin 1 mg(p=0.0001), 3 mg (p<0.0001) and 6 mg (p<0.0001) dose levels comparedwith placebo in the PP analysis set. The observed mean values (±SD)were: placebo 86.0 (38.15); doxepin 1 mg 70.1 (32.78); doxepin 3 mg 66.4(31.56) and doxepin 6 mg 60.2 (28.00). The results using the ITTanalysis set were consistent with those from the PP analysis set.

Secondary

The secondary PSG efficacy assessments are summarized in Table 1. WASOexhibited a statistically significant decrease at the doxepin 1 mg(p<0.0001), 3 mg (p<0.0001), and 6 mg (p<0.0001) dose levels compared toplacebo. SE exhibited statistically significant increases at all threedose levels of doxepin (1 mg, p<0.0001; 3 mg, p<0.0001; 6 mg, p<0.0001)compared to placebo. TST exhibited statistically significant increasesat all three dose levels of doxepin (1 mg, p<0.0001; 3 mg, p<0.0001; 6mg, p<0.0001) compared to placebo. LPS was numerically decreased at the3 mg and 6 mg dose levels. There were no significant differences at anydose level of doxepin compared with placebo for NAASO. WTAS exhibited astatistically significant decrease at the doxepin 3 mg (p=0.0264) and 6mg (p=0.0008) dose levels and numerically reduced at the doxepin 1 mgdose level, all compared to placebo.

TABLE 1 Secondary PSG Efficacy Assessments: Per-Protocol Analysis SetDoxepin Doxepin Doxepin Placebo 1 mg 3 mg 6 mg Parameter Mean MeanP-value^([1]) Mean P-value^([1]) Mean P-value^([1]) Per-Protocol (N =71) WASO (minutes) 99.0 80.5 <0.0001 72.3 <0.0001 65.2 <0.0001 SE(percent) 74.9 78.5 <0.0001 81.0 <0.0001 82.8 <0.0001 TST (minutes)359.4 376.8 <0.0001 388.8 <0.0001 397.4 <0.0001 LPS (minutes) ^([2])27.1 28.3 0.9896 23.7 0.0964 22.4 0.1959 NAASO 12.0 12.3 0.7689 12.80.2801 12.5 0.2742 WTAS (minutes) 13.0 10.4 0.5546 5.9 0.0264 5.0 0.0008WTDS 86.0 70.1 0.0001 66.4 <0.0001 60.2 <0.0001 ^([1])P-value comparingeach active treatment versus placebo using Dunnett's test ^([2]) LPSdata were log-transformed prior to analysis

Thus, 1 mg, 3 mg and 6 mg doxepin demonstrated efficacy on objective andsubjective sleep maintenance parameters in elderly patients (65 years ofage and older) with primary sleep maintenance insomnia, which appearedto be dose-related. Efficacy in delaying early morning awakenings(terminal insomnia) was also demonstrated for doxepin 1 mg, 3 mg and 6mg as evidenced by statistically significant reductions in WTAS at thedoxepin 3 mg and 6 mg dose levels and numerical reductions at thedoxepin 1 mg dose level, all compared to placebo. As demonstrated byTable 2, all doxepin doses were well tolerated and demonstrated anadverse effect profile similar to placebo with no reports ofanti-cholinergic effects or amnesia/memory impairment; no drug-relatedserious adverse events; and no clinically meaningful changes to vitals,physical exams, electrocardiogram or safety labs. No meaningful changesto sleep architecture were observed. There were no significant effectsobserved on next-day residual sedation.

Table 2 summarizes the adverse events as reported by the elderlypatients. The adverse events are arranged by system organ class.

TABLE 2 Adverse Events by MedDRA System Organ Class Safety Analysis SetPlacebo Doxepin HCl 1 mg Doxepin HCl 3 mg Doxepin HCl 6 mg (N = 73) (N =74) (N = 75) (N = 74) Number of Number of Number of Number of Number ofNumber of Number of Number of System Organ Class/Preferred Term PatientsEvents Patients Events Patients Events Patients Events PatientsReporting at Least One Adverse Event  7 (10%) 8  9 (12%) 10 6 (8%) 8 5(7%) 6 NERVOUS SYSTEM DISORDERS 3 (4%) 3 2 (3%) 2 2 (3%) 2 1 (1%) 1SOMNOLENCE 0 (0%) 0 1 (1%) 1 1 (1%) 1 1 (1%) 1 HEADACHE 2 (3%) 2 0 (0%)0 0 (0%) 0 0 (0%) 0 BALANCE DISORDER 1 (1%) 1 0 (0%) 0 0 (0%) 0 0 (0%) 0DIZZINESS 0 (0%) 0 0 (0%) 0 1 (1%) 1 0 (0%) 0 LETHARGY 0 (0%) 0 1 (1%) 10 (0%) 0 0 (0%) 0 PSYCHIATRIC DISORDERS 2 (3%) 2 1 (1%) 1 1 (1%) 1 1(1%) 1 ANXIETY 1 (1%) 1 1 (1%) 1 1 (1%) 1 0 (0%) 0 ABNORMAL DREAMS 1(1%) 1 0 (0%) 0 0 (0%) 0 0 (0%) 0 CONFUSIONAL STATE 0 (0%) 0 0 (0%) 0 0(0%) 0 1 (1%) 1 INFECTIONS AND INFESTATIONS 0 (0%) 0 3 (4%) 3 0 (0%) 0 1(1%) 1 CYSTITIS 0 (0%) 0 1 (1%) 1 0 (0%) 0 0 (0%) 0 DENIAL CARIES 0 (0%)0 0 (0%) 0 0 (0%) 0 1 (1%) 1 FUNGAL INFECTION 0 (0%) 0 1 (1%) 1 0 (0%) 00 (0%) 0 NASOPHARYNGITIS 0 (0%) 0 1 (1%) 1 0 (0%) 0 0 (0%) 0INVESTIGATIONS 2 (3%) 3 1 (1%) 1 0 (0%) 0 1 (1%) 1 ELECTROCARDIOGRAMST-T SEGMENT 1 (1%) 1 1 (1%) 1 0 (0%) 0 0 (0%) 0 ABNORMAL QRS AXISABNORMAL 1 (1%) 2 0 (0%) 0 0 (0%) 0 1 (1%) 1 EYE DISORDERS 0 (0%) 0 1(1%) 1 1 (1%) 1 0 (0%) 0 VISION BLURRED 0 (0%) 0 1 (1%) 1 1 (1%) 1 0(0%) 0 GENERAL DISORDERS AND ADMINISTRATION 0 (0%) 0 1 (1%) 1 1 (1%) 2 0(0%) 0 SITE CONDITIONS ASTHENIA 0 (0%) 0 0 (0%) 0 1 (1%) 1 0 (0%) 0FATIGUE 0 (0%) 0 0 (0%) 0 1 (1%) 1 0 (0%) 0 NON-CARDIAC CHEST PAIN 0(0%) 0 1 (1%) 1 0 (0%) 0 0 (0%) 0 RESPIRATORY, THORACIC AND MEDIASTINAL0 (0%) 0 1 (1%) 1 1 (1%) 1 0 (0%) 0 DISORDERS PHARYNGOLARYNGEAL PAIN 0(0%) 0 0 (0%) 0 1 (1%) 1 0 (0%) 0 WHEEZING 0 (0%) 0 1 (1%) 1 0 (0%) 0 0(0%) 0 MUSCULOSKELETAL AND CONNECTIVE 0 (0%) 0 0 (0%) 0 0 (0%) 0 1 (1%)2 TISSUE DISORDERS SENSATION OF HEAVINESS 0 (0%) 0 0 (0%) 0 0 (0%) 0 1(1%) 2 SKIN AND SUBCUTANEOUS TISSUE 0 (0%) 0 0 (0%) 0 1 (1%) 1 0 (0%) 0DISORDERS SKIN IRRITATION 0 (0%) 0 0 (0%) 0 1 (1%) 1 0 (0%) 0 At eachlevel of summation (overall, system organ class, preferred term),patients reporting more than one adverse event per treatment are countedonly once. Each event is assigned to the most recent treatment recievedprior to onset.

The patients report subjected data, which were consistent with the PSGdata. Subjective WASO (sWASO) was statistically significantly decreasedat all doxepin dose levels (1 mg, p=0.0297; 3 mg, p=0.0144; 6 mg,p=0.0074) compared with placebo. sTST was statistically significantlyincreased at all doxepin dose levels (1 mg, p=0.0182; 3 mg, p=0.0005; 6mg, p<0.0001) compared with placebo. Latency to sleep onset (LSO) wasstatistically significantly decreased at the doxepin 6 mg dose level(p=0.0174), and numerically decreased at the 1 mg and 3 mg dose levelscompared with placebo. Sleep quality was statistically significantlyincreased at all doxepin dose levels (1 mg, p=0.0357; 3 mg, p=0.0019; 6mg, p=0.0047) compared with placebo. The results are summarized in Table3.

TABLE 3 Subjective Sleep Data Doxepin 1 Doxepin Doxepin Placebo mg 3 mg6 mg Parameter (n = 71) (n = 71) (n = 71) (n = 71) sWASO:  89.6 (60.7) 74.3 (55.2)  72.2 (56.4)  71.5 (57.4) Mean (SD) 0.0297 0.0144 0.0074p-value sTST: 339.1 (71.6) 355.7 (63.1) 362.4 (64.3) 369.4 (65.3) Mean(SD) 0.0182 0.0005 <0.0001 p-value LSO:  45.8 (35.9)  42.3 (32.1)  42.4(40.1)  33.9 (24.8) Mean (SD) 0.9961 0.3172 0.0174 p-value sNAASO:  3.2(1.6)  3.2 (2.1)  2.9 (1.7)  3.0 (1.4) Mean (SD) 0.9985 0.3224 0.4080p-value Sleep Quality:  0.5 (1.0)  0.8 (1.0)  0.9 (1.0)  0.8 (1.0) Mean(SD) 0.0357 0.0019 0.0047 p-value

Example 2 A Phase III, Randomized, Double-Blind, Placebo-Controlled,Parallel-Group, Multicenter Study to Assess the Long Term Efficacy andSafety of Doxepin HCl in Primary Elderly Insomnia Patients with SleepMaintenance Difficulties

A phase III, randomized, double-blind, placebo-controlled,parallel-group, multicenter study was conducted to assess the long termefficacy and safety of two dose levels of doxepin 1 mg and 3 mg, inprimary elderly insomnia patients with sleep maintenance difficulties.

Subjects were females and males, 65 years of age or older, with at leasta 3-month history of primary insomnia (as defined in the Diagnostic andStatistical Manual of Mental Disorders, Fourth Edition, Text Revision),who reported experiencing at least 60 minutes of Wake After Sleep Onset(WASO), at least 30 minutes of Latency to Sleep Onset (LSO), and no morethan 6.5 hours of Total Sleep Time (TST) on at least 4 of 7 consecutivenights prior to PSG Screening.

Doxepin 1 mg tablets or 3 mg tablets (lot number 3044567) wereadministered as a single oral dose for 85 consecutive nights during the12-week Double-blind Treatment Period.

Primary Efficacy Variable: The primary efficacy variable was WASO onNight 1.

Additional PSG Variables: Additional efficacy variables assessed on eachPSG recording night during the Double-blind Treatment Period were WASO(Night 15, Night 29, Night 57, and Night 85); WTDS; TST; SleepEfficiency (SE) overall, by third of the night, the last quarter of thenight, and hour of the night; LPS; Latency to Stage 2 Sleep; Number ofAwakenings After Sleep Onset (NAASO) overall and by hour; Total WakeTime (TWT) overall and by hour; Wake Time After Sleep (WTAS); and sleeparchitecture (including percentage and minutes of Stage 1, 2, and 3-4sleep; percentage and minutes of rapid eye movement [REM] and non-REMsleep; and Latency to REM Sleep.)

Subjective Variables: Subjective efficacy variables were subjective TST(sTST), subjective WASO (sWASO), LSO, subjective NAASO (sNAASO), andsleep quality. These variables were assessed using a questionnairecompleted in the morning following each PSG recording night. Drowsiness,ability to function, and total nap time during the day were assessedusing an evening questionnaire completed prior to PSG recording atNights −6, −5, 1, 15, 29, 57, and 85. Other secondary subjectiveefficacy variables included the 2-item Clinical Global Impressions (CGI)scale for severity of illness and therapeutic effect completed by aclinician; the 5-item CGI scale pertaining to therapeutic effectcompleted by the subject; the Insomnia Severity Index (ISI) completed bythe subject, and a subjective assessment of sTST, LSO, and sleep qualitycollected through the IVRS.

Of the 240 randomized subjects, 214 (89%) completed the study. Earlytermination rates and baseline characteristics were comparable acrosstreatment groups. Subjects were female (65%) and male (35%). The meanage was 71.4 years. Subjects were White (80%), Black/African American(9%), Hispanic (9%), Asian (1%), and Other (1%).

Efficacy Results Primary Efficacy Variable (WASO on Night 1) Using theITT Analysis Set

The WASO results are shown in Table 4. Mean WASO on Night 1 wasstatistically significantly decreased following administration ofdoxepin 1 mg and 3 mg compared with placebo. The least-squares (LS) meanWASO was shorter for the doxepin 1 mg and 3 mg groups by 17.8 minutesand 33.8 minutes, respectively, compared with the placebo group.Additionally, in the doxepin 3 mg group the LS mean WASO wasstatistically significantly decreased compared with placebo at eachassessment through 85 nights of treatment. Improvement in WASO on Night1 was independent of sex.

TABLE 4 WASO at Baseline, Night 1 and Night 85: ITT Analysis Set PlaceboDoxepin 1 mg Doxepin 3 mg WASO (minutes) (N = 81) (N = 77) (N = 82)Baseline (mean of 119.5 (37.67) 120.1 (34.97) 117.9 (28.15) Nights −6and −5) Night 1 (Primary n = 81 n = 77 n = 82 Efficacy Variable) Mean(SD) 108.9 (46.01)  91.8 (47.09)  74.5 (37.88) Diff. of LS Mean (Std.−17.8 (6.32)   −33.8 (6.23)   Err.) p = 0.005 p < 0.00 p-value 3 01Night 85 n = 70 n = 69 n = 74 Mean (SD) 109.2 (50.83)  97.0 (44.18) 75.7 (37.55) Diff. of LS Mean (Std. −14.6 (6.80)   −33.2 (6.70)   Err.)p = 0.033 p < 0.00 p-value 0 01 SD = standard deviation. p-valuecomparing each active treatment versus placebo from ANCOVA model thatincluded main effects for treatment and center with the baseline valueas a covariate, using a linear contrast.

Additional Objective Variables

There were statistically significant improvements at multiple timepointson multiple PSG measures of sleep maintenance (including TST, SEoverall, WTDS, and TWT overall) and PSG measures of prevention of earlymorning awakenings (including WTAS. These results are summarized inTable 5.

TABLE 5 Additional Key Objective PSG Efficacy Variables on Night 1 andNight 85: ITT Analysis Set PSG Placebo Doxepin 1 mg Doxepin 3 mgVariable (N = 81) (N = 77) (N = 82) TST (minutes) Baseline 320.6 (40.25)322.4 (39.93) 326.9 (33.16) Night 1 339.7 (54.35) 359.1 (53.05) 382.9(44.23) p = 0.0119 p < 0.0001 Night 85 343.7 (57.72) 360.5 (47.17) 373.7(42.24) p = 0.0257 p = 0.0007 SE Overall (%) Baseline 66.8 (8.39) 67.2(8.32) 68.1 (6.91) Night 1  70.8 (11.32)  74.8 (11.05) 79.8 (9.21) p =0.0119 p < 0.0001 Night 85  71.6 (12.03) 75.1 (9.83) 77.9 (8.80) p =0.0257 p = 0.0007 WTAS (minutes) Baseline  10.1 (14.99)  9.7 (16.31) 9.8 (15.27) Night 1  10.7 (22.63)  8.9 (18.84)  4.7 (14.61) p = 0.6405p = 0.0556 Night 85  12.2 (21.73)  10.8 (21.78)  5.4 (13.20) p = 0.6514p = 0.0284 LPS (minutes)¹ Baseline  49.0 (27.34)  45.4 (25.25)  41.9(22.65) Night 1  39.6 (29.28)  38.8 (29.58)  28.6 (20.53) p = 0.5733 p =0.1079 Night 85  34.9 (32.96)  29.0 (26.45)  37.5 (32.74) p = 0.6493 p =0.0286 Data presented are mean (SD). p-value comparing each activetreatment versus placebo was determined from an ANCOVA model thatincluded main effects for treatment and center with the baseline valueas a covariate, using a linear contrast. ¹Analysis performed onlog-transformed data.

Clinical Global Impressions (CGI)

The Clinical Global Impressions (CGI) consist of two questions addressedto the clinician relating to the severity of illness and therapeuticeffect of the study drug and five questions addressed to the patientrelating to the therapeutic effect of the drug.

CGI Clinician-rated: There were statistically significant improvementsin mean CGI severity of illness and therapeutic effect scores at Night85 in both doxepin treatment groups compared with placebo. Notably, themean CGI severity of illness score decreased by one global category (amean change from moderate severity at baseline to mild severity at Night85) in both doxepin groups. Similarly, the mean CGI therapeutic effectscore was improved by one global category in both doxepin groups. Theseimprovements were not observed in the placebo group for eitherassessment.

CGI Subject-rated: There were statistically significant improvements inCGI therapeutic effect scores compared with placebo in each doxepingroup at each visit for one or more parameters. After 85 nights oftreatment, there were statistically significant improvements for bothdoxepin groups compared with placebo on all five parameters of thesubject-rated CGI scale of therapeutic effect.

Doxepin (1 mg and 3 mg) administered 30 minutes before each subject'sbedtime for up to 85 consecutive nights was safe and well-tolerated.Safety profiles were comparable across the three treatment groups. Therewere no reported deaths during the study or within 30 days followingadministration of the last dose of study medication.

There were no clinically relevant effects on sleep architecture. Sleepstages generally were preserved.

There was no apparent evidence of next-day drowsiness based on meanscores from the DSST, SCT, and VAS for sleepiness, or impairment ofdaytime functioning or daytime drowsiness based on the eveningquestionnaire.

Approximately 40% of subjects in the doxepin 1 mg group and 38% ofsubjects in the doxepin 3 mg group reported a TEAE, compared with 52% ofsubjects in the placebo group. Table 6 summarizes all TEAEs experiencedby greater than or equal to 2% of all subjects.

Overall, both the 1 mg and 3 mg doses demonstrated improvement comparedto placebo. Both doxepin dose levels were safe and well-tolerated withno apparent dose-related effects on safety. These data support the useof doxepin 1 mg and 3 mg in elderly subjects with chronic insomnia.

TABLE 6 TEAEs Experienced by Greater than or Equal to 2 Percent ofSubjects in any Treatment Group: Safety Analysis Set MedDRA System OrganPlacebo Doxepin 1 mg Doxepin 3 mg Class/Preferred Term (N = 81) (N = 77)(N = 82) Subject with any TEAE 42 (52%) 31 (40%) 31 (38%) Infections andInfestations 11 (14%) 12 (16%) 11 (13%) Gastroenteritis 0 (0%) 0 (0%) 3(4%) Nasopharyngitis 1 (1%) 1 (1%) 2 (2%) Bronchitis 2 (2%) 1 (1%) 1(1%) Upper respiratory tract 1 (1%) 2 (3%) 1 (1%) infection Sinusitis 1(1%) 3 (4%) 0 (0%) Urinary tract infection 2 (2%) 2 (3%) 0 (0%) NervousSystem Disorders 16 (20%) 6 (8%)  9 (11%) Headache 11 (14%) 2 (3%) 5(6%) Dizziness 2 (2%) 0 (0%) 2 (2%) Somnolence 4 (5%) 4 (5%) 2 (2%)Gastrointestinal Disorders 10 (12%) 4 (5%) 5 (6%) Dry mouth 2 (2%) 1(1%) 2 (2%) Stomach discomfort 0 (0%) 0 (0%) 2 (2%) Diarrhoea 2 (2%) 2(3%) 0 (0%) Nausea 2 (2%) 0 (0%) 0 (0%) Vascular Disorders 0 (0%) 2 (3%)5 (6%) Hypertension 0 (0%) 1 (1%) 3 (4%) Injury, Poisoning and 5 (6%) 1(1%) 4 (5%) Procedural Complications Fall 0 (0%) 0 (0%) 2 (2%) Jointsprain 1 (1%) 0 (0%) 2 (2%) Respiratory, Thoracic and 5 (6%) 2 (3%) 4(5%) Mediastinal Disorders Pharyngolaryngeal pain 2 (2%) 0 (0%) 0 (0%)Psychiatric Disorders¹ 1 (1%) 1 (1%) 2 (2%) Musculoskeletal and 3 (4%) 1(1%) 2 (2%) Connective Tissue Disorders Back pain 1 (1%) 0 (0%) 2 (2%)¹Psychiatric Disorders SOC included because of its relevance to sleepdisorders. No individual preferred terms within this SOC were reportedby ≥2 subjects in any treatment group.

Example 3 Study to Evaluate Sleep Maintenance Effects of Three DoseLevels of Doxepin Hydrochloride (HCl) Relative to Placebo in AdultPatients (Ages 18-64) With Primary Insomnia

A randomized, multi-center, double-blind, placebo-controlled,four-period crossover, dose-response study was designed to assess theeffects of doxepin (1 mg, 3 mg and 6 mg) compared with placebo inpatients with primary sleep maintenance insomnia.

Patients received a single-blind placebo for two consecutive nightsduring the PSG screening period, and double-blind study drug for twoconsecutive nights during each of the four treatment periods. Followingeach study drug administration, patients had 8 continuous hours of PSGrecording in the sleep center. Patents were allowed to leave the sleepcenter during the day after each PSG assessment was complete. A 5- or12-day study drug-free interval separated each PSG assessment visit.

Patients who qualified for study entry, based on the screening PSGassessments, were randomized to a treatment sequence using a Latinsquare design. A final study visit was performed for patients eitherafter completion of the four treatment periods or upon discontinuationfrom the study. Efficacy assessments were made at each visit and safetyassessments were performed throughout the study.

Sixty-one patients were included in the per-protocol analysis set. Themain inclusion criteria were male and/or female patients, aged 18 to 64years, in good general health with at least a 3-month history ofDSM-IV-defined primary insomnia, reporting each of the following on fourof seven nights prior to PSG screening: ≤6.5 hours of total sleep time(TST), ≤60 min of WASO and ≤20 min of LSO. Doxepin HCl 1 mg, 3 mg and 6mg capsules, and placebo capsules, were provided as a single dose fororal administration.

The primary and secondary efficacy assessments were as described abovein Example 1. All objective efficacy assessments were performed on Night1 and Night 2.

Efficacy Results Primary

WTDS exhibited a statistically significant decrease at the doxepin 3 mg(p<0.0001) and 6 mg (p=0.0002) dose levels compared with placebo. WTDSwas numerically, but not significantly decreased at the doxepin 1 mgdose level. The observed mean values (±SD) were: placebo 51.9 (42.25);doxepin 1 mg 43.2 (28.21); doxepin 3 mg 33.4 (21.87) and doxepin 6 mg35.3 (25.17).

Secondary

The secondary PSG efficacy assessments are summarized in Table 7. WASOexhibited a statistically significant decrease at the doxepin 1 mg(p=0.0130). 3 mg (p<0.0001), and 6 mg (p<0.0001) dose levels compared toplacebo. SE exhibited statistically significant increases at all threedose levels of doxepin (1 mg, p=0.0004; 3 mg, p<0.0001; 6 mg, p<0.0001)compared to placebo. TST exhibited statistically significant increasesat all three dose levels of doxepin (1 mg, p=0.0004; 3 mg, p<0.0001; 6mg, p<0.0001) compared to placebo. Although there were no significantdifferences between doxepin and placebo at ant dose level for LPS, LPSwas numerically decreased, most notably at the 6 mg dose level. Therewere no significant differences at any dose level of doxepin comparedwith placebo for NAASO. WTAS exhibited a statistically significantdecrease a the doxepin 6 mg dose level (p=0.0105) compared to placebo.

Table 7 Secondary PSG Efficacy Assessments: Per-Protocol Analysis SetDoxepin Doxepin Doxepin Placebo 1 mg 3 mg 6 mg Parameter Mean MeanP-value^([1]) Mean P-value^([1]) Mean P-value^([1]) Per-Protocol (N =61) WASO (minutes) 62.1 47.3 0.0130 38.6 <0.0001 38.8 <0.0001 SE(percent) 80.7 84.7 0.0004 86.5 <0.0001 86.9 <0.0001 TST (minutes) 387.5406.5 0.0004 415.2 <0.0001 417.2 <0.0001 LPS (minutes) ^([2]) 34.3 30.10.1836 30.8 0.2783 27.9 0.0681 sTST (minutes) 363.8 364.2 379.7 0.0470383.0 0.0116 sWASO 55.3 56.1 50.5 42.1 0.0109 (minutes) LSO (minutes)50.9 46.9 46.1 44.1 WTAS (minutes) 10.2 4.1 0.1421 5.2 0.0697 2.5 0.0105^([1])P-value comparing each active treatment versus placebo usingDunnett's test ^([2]) LPS data were log-transformed prior to analysis

Thus, doxepin at 1 mg, 3 mg and 6 mg demonstrated efficacy on sleepmaintenance parameters in adult patients with primary sleep maintenanceinsomnia. This effect appeared to be greater in the doxepin 3 mg and 6mg dose groups, with both dose groups having comparable sleepmaintenance efficacy. Doxepin 1 mg, 3 mg and 6 mg also demonstratedefficacy in delaying early morning awakenings (terminal insomnia) asevidenced by significant reductions in WTAS at the doxepin 6 mg doselevel and numerical reductions at the doxepin 1 mg and 3 mg dose levels,all compared to placebo. The doxepin 6 mg dose also demonstrated anumerical improvement on objective sleep onset and a significantimprovement on subjective sleep onset. In general, the pattern of thesubjective efficacy was consistent with the PSG results.

All doxepin doses were well tolerated and demonstrated an adverse effectprofile similar to placebo (See Table 8). There were no significanteffects on clinically meaningful alterations observed on next-dayresidual sedation and sleep architecture.

TABLE 8 Adverse Events by MedDRA System Organ Class Safety Analysis SetPlacebo Doxepin HCl 1 mg Doxepin HCl 3 mg Doxepin HCl 6 mg (N = 66) (N =66) (N = 66) (N = 67) Number of Number of Number of Number of Number ofNumber of Number of Number of System Organ Class/Preferred Term PatientsEvents Patients Events Patients Events Patients Events PatientsReporting at Least One Adverse Event 6 (9%) 7 9 (14%) 13 5 (8%) 6 8(12%) 12 NERVOUS SYSTEM DISORDERS 3 (5%) 3 4 (6%) 5 2 (3%) 2 4 (6%) 5HEADACHE 3 (5%) 3 3 (5%) 3 0 (0%) 0 1 (1%) 1 SOMNOLENCE 0 (0%) 0 1 (2%)1 1 (2%) 1 3 (4%) 3 DIZZINESS 0 (0%) 0 1 (2%) 1 1 (2%) 1 1 (1%) 1INFECTIONS AND INFESTATIONS 2 (3%) 2 1 (2%) 1 1 (2%) 2 0 (0%) 0FOLLICULITIS 0 (0%) 0 0 (0%) 0 1 (2%) 2 0 (0%) 0 GASTROENTERITIS 0 (0%)0 1 (2%) 1 0 (0%) 0 0 (0%) 0 TOOTH INFECTION 1 (2%) 1 0 (0%) 0 0 (0%) 00 (0%) 0 URINARY TRACT INFECTION 1 (2%) 1 0 (0%) 0 0 (0%) 0 0 (0%) 0MUSCULOSKELETAL AND CONNECTIVE 0 (0%) 0 2 (3%) 2 1 (2%) 1 0 (0%) 0TISSUE DISORDERS MYALGIA 0 (0%) 0 1 (2%) 1 1 (2%) 1 0 (0%) 0 BACK PAIN 0(0%) 0 1 (2%) 1 0 (0%) 0 0 (0%) 0 CARDIAC DISORDERS 0 (0%) 0 0 (0%) 0 0(0%) 0 2 (3%) 2 PALPITATIONS 0 (0%) 0 0 (0%) 0 0 (0%) 0 1 (1%) 1VENTRICULAR EXTRASYSTOLES 0 (0%) 0 0 (0%) 0 0 (0%) 0 1 (1%) 1 EYEDISORDERS 0 (0%) 0 1 (2%) 1 0 (0%) 0 1 (1%) 1 EYE REDNESS 0 (0%) 0 0(0%) 0 0 (0%) 0 1 (1%) 1 VISION BLURRED 0 (0%) 0 1 (2%) 1 0 (0%) 0 0(0%) 0 PSYCHIATRIC DISORDERS 0 (0%) 0 0 (0%) 0 0 (0%) 0 2 (3%) 2ABNORMAL DREAMS 0 (0%) 0 0 (0%) 0 0 (0%) 0 1 (1%) 1 ANXIETY 0 (0%) 0 0(0%) 0 0 (0%) 0 1 (1%) 1 RESPIRATORY. THORACIC AND MEDIASTINAL 0 (0%) 01 (2%) 1 0 (0%) 0 1 (1%) 1 DISORDERS NASAL CONGESTION 0 (0%) 0 1 (2%) 10 (0%) 0 0 (0%) 0 PHARYNGOLARYNGEAL PAIN 0 (0%) 0 0 (0%) 0 0 (0%) 0 1(1%) 1 SKIN AND SUBCUTANEOUS TISSUE 0 (0%) 0 1 (2%) 1 1 (2%) 1 0 (0%) 0DISORDERS DERMATITIS 0 (0%) 0 1 (2%) 1 1 (2%) 1 0 (0%) 0GASTROINTESTINAL DISORDERS 0 (0%) 0 1 (2%) 1 0 (0%) 0 0 (0%) 0 STOMACHDISCOMFORT 0 (0%) 0 1 (2%) 1 0 (0%) 0 0 (0%) 0 GENERAL DISORDERS ANDADMINISTRATION 0 (0%) 0 1 (2%) 1 0 (0%) 0 0 (0%) 0 SITE CONDITIONS GAITABNORMAL 0 (0%) 0 1 (2%) 1 0 (0%) 0 0 (0%) 0 IMMUNE SYSTEM DISORDERS 0(0%) 0 0 (0%) 0 0 (0%) 0 1 (1%) 1 HYPERSENSITIVITY 0 (0%) 0 0 (0%) 0 0(0%) 0 1 (1%) 1 INVESTIGATIONS 1 (2%) 2 0 (0%) 0 0 (0%) 0 0 (0%) 0 BLOODPRESSURE INCREASED 1 (2%) 1 0 (0%) 0 0 (0%) 0 0 (0%) 0 CARDIAC MURMUR 1(2%) 1 0 (0%) 0 0 (0%) 0 0 (0%) 0 [1] At each level of summation(overall, system organ class, preferred term), patients reporting morethan one adverse event per treatment are counted only once. Each eventis assigned to the most recent treatment received prior to onset.

Comparison of Results in Elderly vs. Non-Elderly (ages 18-64) Patients

The primary efficacy result, WTDS, was surprisingly significantlydecreased in elderly patients who were given 1 milligram of doxepin. Incontrast, there was no significant effect of 1 mg doxepin in non-elderlyadults. Doxepin at 3 milligrams and 6 milligrams exhibited significantreductions in WTDS in both patient populations.

In addition to the primary efficacy results, two secondary efficacyresults were also affected at lower doxepin dosages in elderly versusnon-elderly patients: LPS and WTAS. LPS exhibited significant decreasesin elderly patients at both 3 milligrams and 6 milligrams doxepin, whileno effect of doxepin on LPS was observed in non-elderly patients atthese dosages. In addition, WTAS exhibited significant decreases inelderly patients at both 3 milligrams and 6 milligrams doxepin, while asignificant decrease in WTAS in non-elderly patients was only observedwith 6 milligrams doxepin.

There were statistically significant improvements in mean CGI(Clinician-rated) severity of illness and therapeutic effect scores atNight 85 in both doxepin treatment groups compared with placebo. Therewere statistically significant improvements in CGl (Subject-rated)therapeutic effect scores compared with placebo in each doxepin group ateach visit for one or more parameters. No such effects were observed inthe non-elderly adults at any dose.

We claim:
 1. A method for treating insomnia in an elderly individual,comprising: identifying an individual over the age of 65 that is at riskof or suffering from next-day residual sedation resulting from a sleepmedication; administering to the individual an initial daily dosage of 3mg doxepin or a pharmaceutically acceptable salt thereof; evaluatingwhether a desired improvement in sleep and avoidance of next-dayresidual sedation is achieved by the individual at the initial dosage;and increasing the dosage to 6 mg only if the desired improvement insleep is not achieved.
 2. A method for treating insomnia in an elderlyindividual, comprising: identifying an individual over the age of 65that is at risk of or suffering from confusion resulting from a sleepmedication; administering to the individual an initial daily dosage of 3mg doxepin or a pharmaceutically acceptable salt thereof; evaluatingwhether a desired improvement in sleep and avoidance of confusion isachieved by the individual at the initial dosage; and increasing thedosage to 6 mg only if the desired improvement in sleep is not achieved.3. A method for treating insomnia characterized by fragmented sleepduring the 8^(th) hour of sleep in an elderly (65 years or older)patient in need thereof, comprising: identifying an elderly patienthaving a sleep maintenance disorder in which, for a given 8 hour periodof desired sleep, the patient experiences fragmented sleep during thefinal 60 minutes of said period, and who is in need of avoidingconfusion or next day residual sedation; evaluating the importance tothat patient of selecting a pharmaceutical agent to minimize the sleepmaintenance disorder; and avoiding the sleep maintenance disorder byreducing fragmented sleep in the 8^(th) hour in said patient by:selecting doxepin therapy for treating the patient based, at least inpart, on its effect on the sleep maintenance disorder; and thenadministering to the patient, prior to the sleep period, doxepin or apharmaceutically accept salt thereof at a beginning dosage of at least 3mg, wherein the dosage is effective to improve sleep maintenanceinsomnia by reducing fragmented sleep during the 8^(th) hour of thesleep period.
 4. The method of claim 3, further comprising identifyingan elderly patient in need of minimizing confusion or next day residualsedation as a side effect of a pharmaceutical treatment.
 5. The methodof claim 3, further comprising selecting the doxepin therapy based, atleast in part, on its low incidence of confusion or next day residualsedation.